The present study summarized recent findings on roles of leptin and endocannabinoids as modulators of the peripheral components of sweet taste. The positive effect of endocannabinoids on sweet sensitivity was opposed to that of leptin which suppresses sweet sensitivity. Leptin and endocannabinoids, therefore, not only regulate food intake via central nervous systems but also may modulate palatability of foods by altering peripheral sweet taste responses via their cognate receptors. Orexigenic and anorexigenic factors such as endocannnabinoids and leptin may affect energy homeostasis by regulating taste sensitivity.

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Gender affects the GH secretory pattern both in normal subjects and in patients with acromegaly by an uncertain mechanism. Here, we report the influence of gender on the relationship between serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly. Seventy-four patients with untreated acromegaly (M/F 27/47, age range 22-86 yr.) were studied. The serum GH levels did not differ between male and female (6.1 vs. 8.7 ng/ml; p=0.26), while serum IGF-I levels, IGF-I SDS and the IGF-I/GH ratio were lower in female than those in male (679 vs. 769 ng/ml; p<0.02, 7.3 vs. 9.2 SDS; p<0.02 and 79.6 vs. 141.5; p<0.05). When the subjects were divided into two groups: age ≤50 yr, and age >50 yr, serum IGF-I levels and IGF-I/GH ratios were lower in female than those in male in patients ≤50 yrs (650 vs. 1002 ng/ml; p<0.05 and 59.8 vs. 142.9; p<0.05), but not in patients >50 yrs (684 vs. 680 ng/ml; p=0.39 and 98.7 vs. 118.4; p=0.40). The GH responses to OGTT, TRH, octreotide, and bromocriptine tests were similar in male and female. In conclusion, IGF-I/GH ratio was significantly lower in female than that in male particularly in younger patients with acromegaly. These data suggest that gender, presumably sex steroids in female, may partially modulate the relationship between circulating IGF-I and GH levels in patients with acromegaly.

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A 70-year old man with a 14 year history of Sjögren syndrome, interstitial pneumonia, and autoimmune hepatitis (AIH) was admitted to our hospital due to hyponatremia with a one month history of fatigue, thirst, and nausea. Laboratory tests on admission revealed that this patient had a central adrenal insufficiency. Pituitary magnetic resonance imaging (MRI) further showed swelling of the stalk and posterior lobe of his pituitary, suggesting infundibulo-hypophysitis. Based on his past history of autoimmune disease, his serum IgG4 levels were measured and found to be remarkably high (924 mg/ dL). Previous biopsy specimens from his liver, lung, and parotid gland were immunostained for IgG4, which revealed a marked infiltration of IgG4-positive plasma cells. As a result of our tests, we made a diagnosis of IgG4-related systemic disease. Interestingly, a subsequent MRI scan at three weeks after the patient commenced glucocorticoid replacement therapy for adrenal insufficiency showed that the swelling of his pituitary stalk was reduced. This finding suggested that IgG4-related hypophysitis may improve either as a result of a supplemental dose of glucocorticoid or possibly spontaneously. Although six cases of IgG4-related hypophysitis have been reported in the scientific literature published in English, our current case is the first in which IgG4-related hypophysitis likely occurred as a result of a long-term history of IgG4-related systemic disease. We report this case herein and review the relevant literature.

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Introduction: This study aims to describe our experiences of parathyroid carcinoma. Materials and Methods: The data of clinicopathological features, surgical treatment and outcomes of seven cases of parathyroid carcinoma among 171 patients who underwent surgery for primary hyperparathyroidism over a 16-year period were analyzed. Results: The major symptoms at the diagnosis included a neck mass in three cases and multiple bone pain in five. Two patients were asymptomatic. No remarkable increases of serum calcium levels were noted in the patients, but serum parathyroid hormone (PTH) concentrations were high in most of the patients (4 of 5 in available). A variety of imaging studies including ultrasonography, sestamibi scan, and computed tomography scan were helpful in identifying the abnormal parathyroid glands, but not specific for the diagnosis of parathyroid carcinoma. In most patients, the parathyroid carcinomas were suspected at the time of neck exploration, and confirmed by final histopathologic examinations. All patients underwent complete surgical excision with curative intent. During the follow-up period, one patient developed lung metastases 6 years later and the other one died of unrelated cause. Conclusion: Preoperative diagnosis of parathyroid carcinoma is difficult, but operative findings are helpful in the diagnosis. The optimal surgical treatment is en block radical resection including adjacent structures when parathyroid carcinoma is suspected. Unusually, although our patients presented with high serum PTH concentrations, they had normal or mild elevated serum calcium concentrations. The reason of why should be investigated in future studies.

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Sulfonylureas are commonly used for the treatment of patients with type 2 diabetes mellitus (T2DM). However, some clinical concerns regarding their use have grown over the past decade. Thus, results of a previous Japan-wide cross-sectional survey of patients with type 2 diabetes mellitus (T2DM) were analyzed to determine the present status and problems associated with the use of sulfonylureas in the treatment of T2DM by general practitioners (GPs) and diabetes specialists. Of 15,652 patients across 721 clinics and hospitals from the previous survey, 15,350 were diagnosed as T2DM (14,312 by GPs and 1,038 by specialists). For each patient, data were collected for HbA1c levels, age, height, body weight, and treatment modality. Of T2DM patients being treated by GPs, 35.4% and 60.0% received sulfonylureas in entire oral drugs or as monotherapy, respectively, compared with 29.2% and 61.2% of patients, respectively, treated by specialists. Of the patients treated with sulfonylurea monotherapy, 1335 patients (35.2%) achieved HbA1c <6.5%, whereas HbA1c was ?8.0% in 531 patients (14.0%). Patients with HbA1c levels ?8.0% had a higher body mass index, used glibenclamide more frequently, and used higher doses of sulfonylureas than patients in whom HbA1c levels were <6.5%. In conclusion, the present study shows that sulfonylureas are central in the treatment of T2DM in Japan. However, careful consideration of suitable patients, agents, and doses is necessary to achieve appropriate glycemic control.

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A novel mutation of insulin receptor gene (INSR gene) was identified in a three generation family with phenotypical variety. Proband was a 12-year-old Japanese girl with type A insulin resistance. She showed diabetes mellitus with severe acanthosis nigricans and hyperinsulinemia without obesity. Using direct sequencing, a heterozygous nonsense mutation causing premature termination at amino acid 331 in the α subunit of INSR gene (R331X) was identified. Her father, 40 years old, was not obese but showed impaired glucose tolerance. Her paternal grandmother, 66 years old, has been suffered from diabetes mellitus for 15 years. Interestingly, they had the same mutation. One case of leprechaunism bearing homozygous mutation at codon 331 was identified. These findings led to the hypothesis that R331X may contribute to the variation of DM in the general population in Japan. An extensive search was done in 272 participants in a group medical examination that included 92 healthy cases of normoglycemia and 180 cases already diagnosed type 2 DM or detected hyperglycemia. The search, however, failed to detect any R331X mutation in this local population. In addition, the proband showed low level C-peptide/insulin molar ratio, indicating that this ratio is considered to be a useful index for identifying patients with genetic insulin resistance. In conclusion, a nonsense mutation causing premature termination after amino acid 331 in the α subunit of the insulin receptor was identified in Japanese diabetes patients. Further investigations are called for to address the molecular mechanism.

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Clomiphene citrate (CC) is known to possess dual actions as an estrogen agonist and an estrogen antagonist. To see how the dual actions of CC are exerted through estrogen receptor α (ERα) and/or ERβ we developed a cell-based transcription assay system in which 293T cells were transfected with the luciferase reporter plasmid with estrogen responsive element and either human ERα or ERβ expression plasmid. CC at lower doses (10^-10 M and 10^-12 M), but not higher doses (10^-6 M and 10^-8 M) elicited estrogenic activity via ERα. However, CC at concentrations between 10^-6 M and 10^-12 M did not elicit any estrogenic activity via ERβ. In the presence of 17β-estradiol (E2), CC behaved either as an agonist or as an antagonist via ERα depending on the concentrations of E2, i.e., antagonistic when combined with the higher E2 concentrations, agonistic with the lower E2 concentrations. On the other hand, via ERβ, CC acted as an estrogen antagonist regardless of the concentration of E2 added together. In conclusion, CC acts as an estrogen agonist/antagonist via ERα in a coexisting estrogen concentration-dependent way whereas it acts as an estrogen antagonist via ERβ whether or not estrogen is present.

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Distant metastasis (DM) at surgery is a prominent prognostic factor in patients with papillary carcinoma of the thyroid. However, the clinical outcomes of these patients (M1 patients) remain unclear. In this study, we investigated the prognosis and prognostic factors of M1 patients. Seventy-one of 5969 patients who underwent initial surgery in Kuma Hospital between 1987 and 2004 were classified as M1 and enrolled in this study. Five-year and 10-year cause specific survival (CSS) rates were 78.8 ± 5.2% and 76.3 ± 5.7%, respectively. Patients aged 55 years or older, having tumor larger than 4 cm, massive extrathyroid extension to adjacent organs other than the recurrent laryngeal nerve and cricothyroid or inferior constrictor muscle, and DM to organs other than the lung showed a significantly worse CSS on univariate analysis. On multivariate analysis, the first three parameters were recognized as independent prognostic factors for M1 patients. Patients who underwent locally curative surgery, having DM showing radioactive iodine (RAI) uptake, and who underwent thyroid stimulation hormone (TSH) suppression therapy showed a better CSS rates than those who underwent only palliative surgery, having DM without RAI uptake, and who did not undergo TSH suppression therapy, although there was no significant difference in CSS between these groups. These findings suggest that evaluation of preoperative and intra-operative findings is important to predict the prognosis of M1 patients, the same as that in patients without DM. Locally curative surgery, RAI therapy, and TSH suppression therapy are actively recommended for M1 patients when conditions permit.

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To examine the association between late-onset hypogonadism (LOH) and metabolic syndrome (Mets) or insulin resistance in the Japanese adult male population, we evaluated anthropometric parameters, indices of glucose and lipid metabolism, and hormones related to sexual function in 274 men (mean age: 46.0 ± 11 years) who underwent general health checks. Seventy subjects (25.5%) were diagnosed as having Mets, while the frequency of LOH was 8.0%. Glycated hemoglobin was normal in the majority of participants (94.9%). The serum free testosterone (FT) level was significantly lower in the Mets (+) group than in the Mets (-) group (11.7 ± 4.0 vs. 14.7 ± 4.6 pg/mL, p<0.0001). FT decreased significantly along with an increase in the number of Mets components. Likewise, the number of Mets components showed a significant difference among the eugonadal, borderline, and hypogonadal groups (2.2 ± 1.4, 1.5 ± 1.4, and 0.9 ± 1.1, respectively). After adjustment for age, body mass index (BMI), and waist circumference (WC), FT was still significantly correlated with Mets (standard partial regression coefficient = - 0.0971; 95 % confidence interval = - 0.1936 ∼ - 0.0006; p = 0.048). A compensatory increase of gonadotropins was not seen in the hypogonadal group. Among Japanese men who were mainly without diabetes, FT was associated with Mets independently of age, BMI, and WC. Mets and insulin resistance may decrease serum testosterone via induction of hypogonadotrophic hypogonadism, and the reduction of testosterone may in turn cause further obesity and insulin resistance, consequently initiating a vicious cycle.

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The aim of this study was to investigate the relationship between RANKL gene polymorphisms and aortic calcification in Korean women. In 237 healthy Korean women, aortic calcification in thoracic and abdominal aorta was examined in simple radiologic method and lumbar spine and femoral neck BMD were examined by dual energy X-ray absorptiometry. Serum OPG levels, bone turnover markers, such as ALP levels and urine deoxypyridinoline levels, and urine calcium excretion were measured. Genotyping of two RANKL gene polymorphisms, rs2277438 and rs9594782, was performed by allelic discrimination using the 5’ nuclease polymerase chain reaction assay. The subjects with CT/CC genotypes of the rs9594782 polymorphism had a 3.9 times higher risk of aortic calcification compared with TT genotype. This significance was significant even after adjustment for age, BMI, blood pressure, fasting plasma glucose, serum highand low-density lipoprotein cholesterol levels. Mean levels of urine deoxypyridinoline were significantly higher in the subjects with AG/GG genotypes of the rs2277438 polymorphism compared with AA genotype, and this significance was persistent even after adjustment for age and BMI. There were no associations of mean values for age, BMI, serum OPG and ALP levels, urine calcium excretion, and BMD with RANKL gene polymorphisms. The RANKL gene rs9594782 polymorphism was associated with aortic calcification in Korean women. Rs2277438 polymorphism showed significant association with urine deoxypyridinoline levels, a bone resorption marker. These results suggest its role on vascular calcification and bone metabolism in humans.

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Pregnancy is a rather rare event in acromegaly because fertility is often reduced during active disease. Previous reports of pregnancy in acromegalic patients showed that the pituitary growth hormone (GH) level was unaffected and the insulin-like growth factor (IGF)-1 level was elevated during the second and third trimesters. We describe here a case of persistent acromegaly that showed suppressed levels of GH and IGF-1 during pregnancy. The suppression of GH secretion and IGF-1 may be due to increased estrogen or other factors circulating in mid- to late pregnancy.

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